Fixation devices for tissue repair

ABSTRACT

Fixation devices for tissue repair, for example sutures, surgical arrows, staples, darts, bolts, screws, buttons, anchors, nails, rivets, or barbed devices comprise at least one of angiogenic material; angiogenic precursor material which is capable of breaking down in vivo to form angiogenic material; or tissue-engineered material, which tissue-engineered material is capable of producing angiogenic material. In a preferred form, the material is incorporated into a polymer matrix having predetermined hydrophobicity to allow controlled release of angiogenic materials such as butyric or hydroxybutyric acid or salts thereof. Polymer matrix compositions comprising angiogenic materials and methods for tissue repair are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application No.61/061,317 filed on Jun. 13, 2008, the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

The invention is concerned with the provision of fixation devices thatimprove tissue repair and with the use of such devices in medicaltreatment. In particular, the invention is concerned with the fixationof tissues, which have limited or no vascular supply, and whereangiogenesis is desirable or a prerequisite for good tissue repair.

2. Related Art

A wide variety of fixation devices exist for use in invasive medicaltreatments. These devices may be used to rejoin, re-affix, hold, orotherwise partake in the repair of tissue during and after surgery andother medical treatments.

An aim of medical practitioners following surgery, for example, is toincite rapid healing and tissue repair throughout the treatment site. Afactor in the promotion of tissue repair is the extent to whichreparative cells and other factors can permeate through to the tissue inquestion. This, in turn, is dependent upon the extent to which bloodvessels can form in and around the site.

The formation of new blood vessels from pre-existing ones is known asangiogenesis. Angiogenesis is an essential process during development ofthe human body, particularly embryonic development. Development of thehuman embryo commences with fusion of blood islands into vascularstructures in the process of vasculogenesis; subsequently angiogenesisbegins, with new vessels sprouting off from the vessels formed duringvasculogenesis. Angiogenesis normally tails off, however, when the bodybecomes adult. With the exception of the female reproductive system,angiogenesis in the adult mainly occurs during tissue repair afterwounding or inflammation, although it is also associated with adultpathological conditions, such as tumor growth, rheumatoid arthritis,psoriasis, and diabetes.

The principle cell type involved in angiogenesis is the microvascularendothelial cell. Following injury and/or in response to angiogenicfactors, the basement membrane of endothelial cells in the parent bloodvessel is degraded, a process mediated by endothelial cell proteases.Once the basement membrane is degraded, endothelial cells migrate outinto the perivascular space. Cells at the base of the sprout proliferateand replace the migrated cells. A new basement membrane is then formedand two contiguous sprouts fuse together to form a loop. Subsequently alumen forms and blood begins to flow.

The endothelial cell is the central cell type involved in angiogenesisbecause it is capable of expressing all the necessary information forthe formation of new microvascular networks. It appears to achieve thisby acting in concert with many different cell types to form new vessels.While not wishing to be bound by any theory, these other cell types maypromote angiogenesis by expressing growth factors and cytokines thatstimulate the proliferation and migration of the primary cellularcomponents of the vascular wall, including endothelial cells.

Therapeutic angiogenesis is the clinical use of angiogenic factors or,in some cases, genes encoding these factors to enhance or promote thedevelopment of blood vessels in ischaemic/avascular tissue. The idealagent for therapeutic angiogenesis would be safe, effective,inexpensive, and easy to administer. It would also be highly desirableto provide angiogenic factors in a controlled way over a predeterminedperiod of time.

It is an aim of the present invention to provide medical devices, whichrelease angiogenic factors that promote blood vessel formation in thesurrounding tissue.

It is a further aim of the present invention to provide fixation deviceswhich promote tissue repair in the surrounding tissue and which willrelease factors that promote blood vessel vaso-dilation. Delivery ofsuch factors or pharmacological active agents using fixation devices,for example a suture or surgical tape, requires the suture or surgicaltape to have certain characteristics to enable it to function as both asuture or surgical tape and a fixation or delivery device. For instance,the suture must have adequate strength, knot tying and slidingproperties for it to Junction in its primary role, as a suture. As abiological agent delivery device, the suture must be able to incorporatethe active agent within its structure in such a way that the activeagent is not changed in any way during the loading. The active agentmust be stable within the structure to allow for normal storage prior touse. Once in place in vivo the active agent must be released at acertain dose over a certain time period to maximise its therapeuticproperties and minimise adverse reactions. Suture repair, using astandard suture, of certain tissues which have limited or no vascularsupply, for example, meniscal cartilage, articular cartilage, ligaments,tendons, bone, and ischaemic tissue can be problematic.

SUMMARY

In one aspect of the invention, the invention relates to a fixationdevice for tissue repair including at least one of angiogenic materialor angiogenic precursor material which is capable of breaking down invivo to form angiogenic material, wherein the angiogenic material is inadmixture with polypropylene.

In an embodiment, the angiogenic material includes one or more ofbutyric acid, butyric acid salt, α-monobutyrin, α-dibutyrin,β-dibutyrin, tributyrin, or hydroxybutyrate. In another embodiment, thebutyric acid salt is selected from sodium, potassium, calcium, ammonium,and lithium salts. In yet another embodiment, the angiogenic materialincludes one or more of the following angiogenic factors: angiogenicpeptide growth factors, including autologous, xenogenic, recombinant,and synthetic forms of these, including the vascular endothelial growthfactors VEGF 121, 165, 189 and 206; fibroblast growth factors FGF-1,FGF-2, FGF-7 (keratinocyte growth factor); transforming growth factorfamily (TGF-α, -β); platelet derived growth factors PDGF-AA, PDGF-BB,and PDGF-AB; platelet derived endothelial cell growth factor (PD-ECGF);hypoxia inducible factor-1 (HIF-1); scatter factor (SF, also known ashepatocyte growth factor or HGF); placenta growth factor (PIGF)-1, -2;tumor necrosis factor α (TNF-α); midkine; pleiotrophin; insulin-likegrowth factor-1; epidermal growth factor (EGF); endothelial cell growthfactor (ECGF); endothelial stimulating angiogenic factor (ESAF);connective tissue growth factor (CTGF); CYR61; Angiogenin; orAngiotrophin.

In a further embodiment, the angiogenic material includes one or moreblood clot breakdown products, including thrombin, heparin, andautologous, allogeneic, xenogeneic, recombinant, and synthetic forms ofthese materials. In yet a further embodiment, the angiogenic materialincludes one or more of hyaluronan, para-thyroid hormone, angiopoietin1, del-1, erythropoietin, fas (CD95), follistatin, macrophage migrationinhibitory factor, monocyte chemoattractant protein-1, and nicotinamide.In an embodiment, the angiogenic precursor material includes one or moreof fibrin, including autologous, allogeneic, xenogeneic, recombinant andsynthetic forms thereof, and hyaluronic acid.

In another embodiment, the fixation device is coated on at least oneexternal surface with one or more of the angiogenic material, theangiogenic precursor material, or the tissue-engineered material. In yetanother embodiment, the fixation device has at least one of theangiogenic material, the angiogenic precursor material, and thetissue-engineered material impregnated into at least one region thereof.In a further embodiment, the fixation device includes a suture, asurgical arrow, a staple, a dart, a bolt, a screw, a button, an anchor,a nail or rivet, or a barbed surgical device.

In another aspect, the present invention relates to a method oftreatment of a mammalian organism in clinical need thereof, includingthe step of implanting a fixation device into a tissue defect in themammalian organism, the fixation device including at least one ofangiogenic material or angiogenic precursor material which is capable ofbreaking down in vivo to form angiogenic material, wherein saidangiogenic material is in admixture with polypropylene.

In an embodiment, the tissue into which the fixation device is implantedis avascular tissue. In another embodiment, the tissue is meniscalcartilage, articular cartilage, ligament, bone, or ischaemic tissue.

In yet another aspect, the present disclosure relates to a compositionof matter. The composition includes a blend of polypropylene and awater-soluble or water miscible angiogenic material or angiogenicprecursor in a therapeutically effective amount sufficient to promoteangiogenisis. In an embodiment, the angiogenic material includes one ormore of butyric acid, hydroxybutyric acid, the sodium, potassium,calcium, ammonium and lithium salts and polymers of said acids, ormonobutyrin. In yet another embodiment, the composition contains up toabout 12% by weight of the angiogenic material.

Further features, aspects, and advantages of the present invention, aswell as the structure and operation of various embodiments of thepresent invention, are described in detail below with reference to theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and form a part ofthe specification, illustrate the embodiments of the present inventionand together with the description, serve to explain the principles ofthe invention. In the drawings:

FIG. 1 illustrates a tear in the red-white zone of meniscal cartilage.

FIG. 2 shows results from biomechanical tests performed on treatedmenisci.

FIG. 3 shows cumulative release rates of butyrate from size 5-0 and size6-0 monofilaments.

FIG. 4 shows the release rate of butyrate from two different batches ofNo. 2 suture.

FIG. 5 shows the release rate of sodium butyrate from three differentconfigurations of size No. 0 sutures.

FIG. 6 shows the release rate of butyric acid from different polymercompositions.

FIGS. 7A-7C illustrate a patellar tendon repair procedure on a sheeplimb.

FIG. 8 shows the mechanical testing results of tendon healing after therepair shown in FIGS. 7A-7C.

FIGS. 9A and 9B illustrate control and butyric acid containing suturerepaired tendon-bone interfaces.

DETAILED DESCRIPTION OF THE EMBODIMENTS

As used herein, the term “angiogenic material” is to be understood toinclude not only material comprising one or more angiogenic factors butalso materials which stimulate blood supply by inducing vaso-dilation ofpre-existing vascular material.

As used herein, the term “angiogenic factor” is to be understood toinclude materials, which directly or indirectly promote angiogenesis,for example, materials that are capable of breaking down in vivo to formangiogenic material.

As used herein, the term “angiogenesis” is to be understood to includethe growth of new blood vessels from existing ones.

As stated above, the angiogenic material comprises one or moreangiogenic factors. A first class of angiogenic factors, which fallswithin the scope of the invention, comprises angiogenic peptide andprotein growth factors, including autologous, allogenic, xenogenic, andrecombinant and synthetic forms of these. This class includes thevascular endothelial growth factor family, particularly VEGF 121, 165,189 and 206; fibroblast growth (actor family, particularly FGF-1, FGF-2,FGF-7 (keratinocyte growth factor); transforming growth factor family(TGF-α, -β);, platelet derived growth factor, particularly PDGF-AA,PDGF-BB and PDGF-AB; platelet derived endothelial cell growth factor(PD-ECGF); hypoxia inducible factor-1 (HIF-1); scatter factor (SF, alsoknown as hepatocyte growth factor or HGF); placenta growth factor(PIGF)-1, -2; tumour necrosis factor-α (TNF-β); midkine; pleiotrophin;insulin-like growth factor-1; epidermal growth factor (EGF); endothelialcell growth factor (ECGF); endothelial stimulating angiogenic factor(ESAF); connective tissue growth factor (CTGF); CYR61; Angiogenin; orAngiotrophin.

A second class of angiogenic factors which falls within the scope of theinvention comprises blood clot breakdown products, such as thrombin andheparin including autologous, allogeneic, xenogeneic, and recombinantand synthetic forms of these materials.

A third class of angiogenic factors which falls within the scope of theinvention comprises those based around butyric acid, including:

-   -   butyric acid (butanoic acid, C₄H₈O₂) and butyric acid salts,        including sodium, potassium, calcium, ammonium, and lithium        salts    -   butyric acid derivatives and polymers containing butyric acid        residues    -   α-monobutyrin (1-glycerol butyrate; 1-(2,3 dihydroxypropyl)        butanoate; C₇H₁₄O₄)    -   α-dibutyrin (1,3-glyceroldibutyrate; 1,3-(2        hydroxypropyl)dibutanoate; C₁₁H₂₀O₅)    -   β-dibutyrin (1,2-glyceroldibutyrate; 1,2-(3        hydroxypropyl)dibutanoate; C₁₁H₂₀O₅)    -   tributyrin (glycerol tributyrate; 1,2,3-propyl)tributanoate;        C₁₅H₂₆O₆)    -   hydroxybutyrate and polymers containing hydroxybutyric acid        residues.    -   The compounds disclosed in PCT International Patent Application        Publication WO 90/11075, the disclosure of which is incorporated        herein by reference in its entirety, are also expressly included        in the scope of the present invention. These have general        formula:

-   -   wherein X is O, NH, S, or CH₂, and R¹ is alkyl or acyl of 2-10C        which is saturated or unsaturated and which is unsubstituted or        substituted with one or more substituents which do not interfere        with angiogenic activity, said substituents selected from the        group consisting of OH, OR, SH, SR, NH₂, NHR, NR₂, and halo        wherein each R is independently lower alkyl (1-4C); and each R²        and R³ is independently H, PO₃ ⁻², or is alkyl or acyl as        defined above, or in formula 1, R², and R³ taken together are an        alkylene moiety or OR² and OR³ form an epoxide, which amount is        effective to stimulate angiogenesis in said subject.    -   wherein R² and R³ are acyl or H    -   wherein said acyl group is CH₃(CH₂)_(n1)CO, wherein n1 is an        integer of 0-8; or is neopentoyl or cyclohexylcarbonyl    -   wherein, in the compound of formula 1, R², and R³ taken together        are

-   -    wherein n2 is an integer of 0-7    -   the method stated above wherein one of R² and R³ is H and the        other is alkyl (1-10C)    -   the method stated above wherein X is O    -   the method stated above wherein R¹ is acyl (2-6C)

A fourth class of angiogenic factors, which falls within the scope ofthe invention, comprises inflammatory mediators. These materials promotetissue inflammation, which in turn promotes angiogenesis. Included inthis class are tumor necrosis factor α (TNF-α); prostaglandins E1 andE2; interleukins 1, 6, and 8; and nitric oxide.

Disparate other angiogenic factors are known which do not fall into anyclass. Included in this group are hyaluronan, para-thyroid hormone,angiopoietin 1, del-1, erythropoietin, fas (CD95), follistatin,macrophage migration inhibitory factor, monocyte chemoattractantprotein-1, transferring, and nicotinamide.

The fixation devices of the invention aptly comprise angiogenicprecursor material, which is capable of breaking down in vivo to formangiogenic material. Angiogenic precursor materials according to theinvention include fibrin, including autologous, allogeneic, xenogeneic,recombinant and synthetic forms thereof, and hyaluronic acid.Degradation fragments of fibrin found to have advantageous angiogenicproperties include fragments D and E.

Alternatively, the fixation devices of the invention may comprisetissue-engineered material, which tissue-engineered material is capableof producing angiogenic material. Tissue-engineered material fallingwithin the scope of the invention includes material capable of producingangiogenic material comprising angiogenic factors contained within thefirst class of angiogenic factors (see above). Tissue-engineeredmaterial according to the invention includes, without limitation,proprietary products such as DERMAGRAFT™ and TRANSCYTE™.

Advantageously, the angiogenic material is present in an amount that istherapeutically effective for the mammalian organism in question.Preferably, the angiogenic material is present in an amount that istherapeutically effective for humans. As used herein, the term“therapeutically effective amount” is to be understood to meansufficient to cause or increase the rate of angiogenesis. Whatconstitutes a therapeutically effective amount is specific to theangiogenic factor(s) comprised within the angiogenic material. In thecase of VEGF and FGF-2, for example, the fixation device should compriseup to 50 μg of factor per mg of device, preferably less than 25 μg/mg.

The term “fixation device” includes any devices used to rejoin,re-affix, hold or otherwise partake in the repair of tissue. Anon-exhaustive list of such devices includes sutures, surgical arrows,staples, darts, bolts, screws, buttons, anchors, nails, rivets or barbeddevices. The fixation devices of the invention also include augmentationdevices such as cuffs which are used to promote angiogenisis at theinterface of different tissue types such as ligament and bone or tendonand muscle.

Ways of incorporating the angiogenic material into or onto devicesaccording to the invention include the following:

The fixation devices according to the invention may be impregnated withangiogenic material after manufacture of the fixation device.Impregnation may result in angiogenic material being distributedthroughout up to the whole of the fixation device. Distribution of theangiogenic material may be homogenous or inhomogenous. In the lattercase, the fixation device would comprise localised regions comprisinghigher concentrations of angiogenic material. Preferably, impregnationresults in angiogenic material being present in at least a regionextending into the device from at least one of its external surfaces.More preferably, impregnation results in angiogenic material beingdistributed throughout the whole of the fixation device. Whether theangiogenic material is distributed homogenously or inhomogenouslythroughout the device and, if inhomogenously, what form the distributionprofile has, will depend on the effects to be achieved. In particular,the distribution profile will strongly influence the release profile ofangiogenic material into the surrounding tissue.

Impregnation methods, which may be used according to the invention,include, without limitation, dipping, soaking, and under vacuum, ifappropriate.

In a second embodiment, the angiogenic factor, material or precursortherefore may be physically incorporated into the main fabric of thefixation device. Aptly, therefore, the angiogenic material willconstitute discrete zones within the fabric of the fixation device.Suitably, threads or filaments of angiogenic material may be co-spun orwoven together with fibrous or filamentary material comprising the mainfabric of the fixation device. For example, threads of angiogenicmaterial may be braided with polyethylene terephthalate or ultra highmolecular weight polyethylene fibres used to produce a suture.Alternatively, the angiogenic material may be co-extruded with the mainfabric material of the fixation device.

In a third embodiment, the angiogenic material may be coated eitherdirectly onto at least one of the external surfaces of the fixationdevice after manufacture of the fixation device or, alternativelyincorporated into a carrier, from which its release can be controlled,and then coated directly onto the fixation device.

Preferably, where the angiogenic factors, materials, or precursors arecoated onto or formed as discrete components or zones within thefixation device, they may be first formulated with a hydrophobic polymerto be delivered under controlled release conditions by a diffusionmechanism from the monolithic matrix comprising the factor andhydrophobic polymer. Thus, for example, by incorporating a watermiscible or soluble angiogenic material into a polymer matrix, which ishydrophobic in nature, the release rate of the angiogenic material canbe controlled. Water is required to solubilise the material, therebysubsequently releasing the material. The degree of hydrophobicity of thepolymer matrix controls the rate of water permeation, and hence the rateof release of the angiogenic material.

Preferably, the hydrophobic polymer matrix is polypropylene. Typically,the angiogenic material is blended into the polypropylene forming amixture which is then drawn into a monofilament. Monofilaments can betwisted or braided to form multifilaments. Preferably, the mixture ofangiogenic material and polypropylene monofilaments are co-braided withother polymer fibres or monofilaments, including, without limitation,ultra high molecular weight (UHMW) polyethylene or polyester fibres ormonofilaments to form a suture.

Factors which influence the release rate of the angiogenic materialinclude the choice of angiogenic material, the quantity of angiogenicmaterial blended into the polypropylene matrix (also known as theangiogenic factor loading), and the diameter of the monofilaments.

For the purposes of this invention, the hydrophobic polypropylene matrixis used with butyric acid or a butyric acid salt. The salts of butyricacid are inherently stable and have a low volatility. Although thehydrophobic polypropylene matrix may be used with any angiogenicmaterial having appropriate water solubility or miscibility.

Effective use of butyric acid (or salts thereof) as an angiogenicmaterial has not been previously demonstrated. There are two possiblereasons for this. The first is that butyric acid has a particularlypungent smell and is unpleasant to use. The second reason is the findingthat butyric acid is so rapidly biodegraded that it is unable toeffectively promote angiogenesis before it is broken down to ineffectivemetabolites.

We have found that by formulating butyric acid or water soluble/misciblesalts thereof with polypropylene, the noted disadvantages are avoided.The angiogenic material can be delivered at a controlled dosage rate inamounts, which are not malodorous.

Hydroxybutyric acid and derivatives, salts, and polymers thereof, andthe butyrin derivatives, such as monobutyrin, may also be formulatedwith polypropylene.

Thus in accordance with another aspect of the invention there isprovided a composition of matter comprising a blend of polypropylene anda water-soluble or water miscible angiogenic material or precursortherefor in a therapeutically effective amount sufficient to promoteangiogenisis.

For the purposes of this invention, the composition of matter comprisesa blend of polypropylene and butyric acid or a water-soluble or watermiscible salt thereof in a therapeutically effective amount sufficientto promote angiogenisis.

Water-soluble or water miscible derivatives of butyric or hydroxybutyric acid, which are suitable for the compositions of matter of theinvention, include the sodium, potassium, calcium, ammonium, and lithiumsalts.

Polypropylene will suitably be admixed or bended with up to about 12% byweight, more suitably up to about 7% by weight, of the angiogenicmaterial.

Polypropylene containing the angiogenic factor can be used as a coatingfor any fixation device.

The angiogenic material may be coated onto all external surfaces of thefixation device. Coating methods, which may be employed, include dipcoating and spray coating.

The present invention further provides a method for the repair ofdamaged tissue comprising the step of implanting a device in accordancewith the invention into a tissue defect.

Preferably, the tissue into which the fixation device is implanted is ofminimal vascularity. More preferably, the tissue is meniscal cartilage,articular cartilage, ligament, tendon, bone, or ischaemic tissue. Thefixation devices of the invention may be used at the interface ofdifferent tissue types, for example between ligament and bone or betweenmuscle and tendon.

The invention will be illustrated by the following Examples.

EXAMPLE 1

O Ti-Cron™ braided sutures, which are non-resorbable and shouldtherefore have no significant effect on angiogenesis, were impregnatedwith either butyric acid or monobutyrin. The butyric acid impregnatedsutures gave a release rate in the range of 25-3000 ng per cm of suture,or 25-3000 ng butyric acid per 1.4 mg of suture per day for 21 days. Thesutures were impregnated by soaking them for at least 7 days in a stocksolution of butyric acid. The monobutyrin impregnated sutures gave arelease rate in the range of 25-3000 ng per cm of suture, or 25-3000 ngmonobutyrin per 1.4 mg of suture per day for 7 days. Prior to thesurgery the sutures were removed from the stock solution and wiped twicewith a surgical swab,

Blue Faced Leicester Cross Suffolk Tubs were employed for this example.This is a fairly robust species of sheep with large long bones.Anatomically sheep bones closely approximate to those of man and areregularly used as models for bone graft substitutes and healing. Thesurgical procedure to implant the suture involved the meniscus beingaccessed by a standard medial arthrotomy. Using a scalpel, an 8 mm fullthickness longitudinal tear was created in the red-white zone of one ofthe medial menisci.

The tear was then sutured using (i) a 0 Ti-Cron suture which had beenimpregnated with butyric acid, as detailed above, or (ii) a 0 Ti-Cronsuture which had been impregnated with monobutyrin, as detailed above,or (iii) a control untreated 0 Ti-Cron suture which did not containbutyric acid or monobutyrin. The suture technique used was an outside-inhorizontal mattress suture. Joints were then closed and the animalsallowed to recover.

The animals were permitted to put weight on the joints immediatelythereafter and were terminated at the 6 week time point.

FIG. 1 of the accompanying drawings illustrates a tear, which cutsthrough the red-white zone of meniscal cartilage, made as describedsupra. FIG. 1 shows a haematoxylin and phloxine stained histologicalsection. The repaired tear is roughly indicated by dotted line (1),which is a red-white tear. The site of the suture location can be seenin the section (3). Angiogenesis (2) in the form of migratingendothelial cells and newly formed blood vessels can be observed as canhealing of the tear.

It is the form taken by the angiogenesis which is the best indicator ofthe success of this experiment: as discussed above, angiogenesis is theformation of new blood vessels from existing ones. This means thatangiogenesis could only be observed radiating out from existing bloodvessels in the red zone and in fact what is observed is a steady frontof new blood vessels (2) advancing from the red zone through thetransitional zone towards the white zone.

With reference to FIG. 2, biomechanical evaluation was performed ontreated menisci biopsied after 6 weeks in-vivo. The test was based onexperiments performed by Roeddecker et al. (1994) which involvedcircumferentially tearing menisci and measuring average tear loads andaverage tear energies of the repaired areas.

Initially, an incision of approximately 5-10 mm was made in theposterior horn of each meniscus to produce two “free ends”. Thisincision was positioned to align with, and meet, the repaired area ofmeniscus. Fully repaired areas of meniscus were sometimes hard toidentify, so the incision was positioned according to best judgement.The sutures used to initiate the repair were exposed at the periphery ofthe meniscus and the suture knots were removed.

Testing was performed using the Instron 5566 materials test machine. The“free ends” of each meniscus were gripped using pincer grips and a 100 Ncapacity load cell was used to measure the resultant tear loadthroughout the test. Once complete, the average tear load, from theforce/displacement curve, was identified using two cursors and the tearenergies under this same area of the force/displacement curves wereautomatically calculated.

Three control menisci were tested, where the repairs were initiated withuntreated suture, three were tested where the suture had beenimpregnated with butyric acid, and three were tested where the suturehad been impregnated with monobutyrin.

The sutures impregnated with an angiogenic factor substantiallyincreased the strength of the repair tissue above that of the untreatedcontrol. Normal meniscal tissue has a tear strength of 14 N/mm

EXAMPLE 2 Monofilament Suture

Polypropylene (ECM Plastics) and sodium butyrate (Alfa Aesar, Purity:99%) were mixed in a Leistritz twin screw extruder. Four mixtures weremade, each one containing 2.5, 5, 7.5 and 10% w/w of sodium butyrate.The mixtures were extruded to form rods which were then furtherprocessed to form pellets. The pellets were then extruded into USP size5-0 monofilaments, (USP sizes defined in USP 29, 2006). Pellets formedfrom the 5% w/w mixture were also extruded into USP size 6-0monofilaments.

The total sodium butyrate content of the monofilaments was measured byliquid chromatography (HPLC) following extraction in de-ionised water at90° C. To determine the release rate and total release of sodiumbutyrate(NaB) from the monofilaments, monofilaments of 20 inch lengthwere placed in phosphate buffered saline (PBS) at 37° C. Analysis of thePBS for the presence of butyrate was carried out by HPLC every day overa period of 28 days. After each analysis, the PBS was replaced withfresh PBS.

The sodium butyrate content for the 5-0 monofilaments was found to bewithin the range of 1.9 to 7.5 % w/w. The 6-0 monofilament was found tohave a total sodium butyrate content of 4.1% w/w. FIG. 3 illustrates thecumulative release rates from the 5-0 monofilaments. It was found thatthe release rate of the sodium butyrate from the 5-0 monofilamentsdepended on both the suture diameter and the initial concentration ofthe sodium butyrate. In all cases, the release of the sodium butyratewas exhausted after approximately 28 days.

EXAMPLE 3

Braided Suture

Polypropylene (ECM Plastics) and sodium butyrate (Alfa Aesar, Purity:99%) were mixed in a Leistritz twin screw extruder. Mixtures containing5 and 7.5% w/w of sodium butyrate were made. The mixtures were extrudedto form rods which were then further processed to form pellets. Thepellets were then extruded into USP size 5-0 monofilaments and USP size6-0 monofilaments.

Three end USP size 6-0 monofilaments of 5% w/w sodium butyrate were thenbraided with ultra high molecular weight polyethylene filaments to forma mixed, sized No. 2 braded suture. A sized No. 0 braided suture wasalso manufactured using three different monofilament/polyethylene mixes.The three size 0 sutures had either one or two ends of USP size 5-0monofilaments of 7.5% w/w sodium butyrate, or two ends of USP size 6-0monofilaments of 5% w/w sodium butyrate braided with ultra highmolecular weight polyethylene filaments.

The total sodium butyrate content of the sutures was measured by liquidchromatography (HPLC) following extraction in de-ionised water at 90° C.To determine the release rate and total release of sodium butyrate fromthe sutures, weighed lengths of each suture were placed in phosphatebuffered saline (PBS) at 37° C. Analysis of the PBS for the presence ofbutyrate was carried out by HPLC over a period of 28 or 56 days. Aftereach analysis, the PBS was replaced with fresh PBS.

FIG. 4 illustrates the release rate of butyrate from two differentbatches of the No. 2 suture. The two batches gave similar release ratesup to approximately 21 days and demonstrated the consistency of both themanufacture of the suture and the release of the sodium butyratetherefrom.

EXAMPLE 4

FIG. 5 illustrates the release rate of sodium butyrate from the threeconfigurations of the sized No. 0 sutures of Example 3. The composition,size, and number of the monofilaments within the suture were found toinfluence both the release rate and total release of the sodium butyratefrom the suture.

EXAMPLE 5

Butyric acid and salts thereof were formulated with different polymercompositions and the rate of release into PBS determined.

Example 5a: Sutures made from 0 Ti-Cron were soaked in solutions ofbutyric acid (50,000 μg cm⁻³). After 66 h, the sutures were removed fromthe butyric acid solution and placed in 2 ml of PBS. The PBS wasreplaced on a daily basis for up to seven days and then at 2 and 3 weektimepoints. The isolated PBS extracts were analysed for butyric acidcontent using an HPLC method. Over 90% of the butyric acid was releasedwithin the first four days (FIG. 6).

Example 5b: Sodium butyrate (1% w/w) was compounded into poly (L) lacticacid (PLLA) and then rods of the polymer extruded. The release rate ofbutyric acid form these rods was evaluated as described above. Butyricacid was released rapidly from the PLLA into PBS (FIG. 6).

Example 5c: Calcium butyrate (1% w/w) was compounded into anethylene-vinyl acetate copolymer (33% by weight vinyl acetate content)and then rods of the polymer extruded. The release rate of butyric acidfrom these rods was evaluated as described above. Thus it can be seenthat by altering the hydrophobicity of the polymer, the release rate ofan angiogenic factor can be controlled (FIG. 6).

EXAMPLE 6

Acute repair in a sheep was performed using the patellar tendon. Thesurgical protocol used for this repair can be found in Newsham-West R,Nicholson H, Walton M, Milburn P. Long-term morphology of a healing bonetendon interface: a histological observation in a sheep model, Journalof Anatomy, Vol. 210, (2007), pp. 318-327, the disclosure of which isincorporated herein by reference in its entirety. Prior to the surgicalrepair, the sheep knee joint was immobilized in 5°-10° of flexion toprevent tensile loading of the patellar tendon during healing. Once thejoint was immobilized, the tendon was pared off the tibial bone with ascalpel blade. The exposed bone surface was scraped clean of anyremaining tendon and then gently ground with a dental bur until therewas a slight vascular blush. Two holes were then made in the tibial bonevia the use of a drill. The prepared bone bed is shown in FIG. 7A. Asshown in FIG. 7B, two suture anchors were then implanted into the holesof the prepared bone bed. The anchor sutures were then passed verticallythrough the tendon, as shown in FIG. 7C, and the sutures were tied inorder to secure the tendon onto the bone surface. External fixation wasapplied to the surgical area and knee immobilization was maintained for3 weeks post-surgery,

After 3 weeks, the external fixation was removed and the animals wereallowed to return to full weight bearing. The sutures used in theanchors were braided sutures made from monofilaments that had beenextruded from polypropylene compounded with sodium butyrate. Prior tothe repair, the braided suture material was tested for total sodiumbutyrate content and butyric acid release over time. All samples weretested in quadruplicate. Finished test suture was found to contain onaverage 7.4 μg/cm sodium butyrate (range of 6.6-9.0 μg/cm) and butyricacid release from the suture was detectable for 28 days in vitro,thereby demonstrating an extended release.

A second identical repair was done with suture anchors that includedsuture made from polypropylene monofilaments that had been extruded onlyfrom polypropylene and had not been compounded with sodium butyrate.This suture was used as a control.

After 12 weeks, mechanical testing of tendon healing was performed. Thetesting demonstrated that the use of a butyric acid containing suture ina simple suture configuration repair lead to a statistically significant(p<0.01) enhancement (41%) of the strength to failure properties of therepaired bone to tendon interface when compared to the control suture inthe same simple configuration. It was observed that the enhancement instrength to failure with butyric acid containing sutures was similar torepairs using a more complex footprint suture configuration. As shown inFIG. 8, there was a 41% increase with butyric acid and a 31% increasewith modified footprint suture configuration compared to the simpleconfiguration with the control suture.

Histologically, the control and butyric acid containing suture repairedtendon-bone interfaces look similar with some evidence of increasedosteogenic activity in the butyric acid suture samples. FIG. 9Arepresents the control suture repaired tendon-bone interface and FIG. 9Brepresents the butyric acid containing suture repaired tendon-boneinterface. The dotted lines in FIGS. 9A and 9B represent the bone totendon interface.

In conclusion, the butyric acid containing suture enhanced tendon tobone healing, when compared to the control suture, as measured bymechanical testing of the strength to failure of the tendon-boneinterface after twelve weeks of healing in an acute model of tendonrepair in a sheep. This data supports the conclusion that the use of apro-angiogenic suture represents a viable approach for improving tendonto bone healing.

The embodiments were chosen and described in order to best explain theprinciples of the invention and its practical application to therebyenable others skilled in the art to best utilize the invention invarious embodiments and with various modifications as are suited to theparticular use contemplated.

As various modifications could be made in the constructions and methodsherein described and illustrated without departing from the scope of theinvention, it is intended that all matter contained in the foregoingdescription or shown in the accompanying drawings shall be interpretedas illustrative rather than limiting. Thus, the breadth and scope of thepresent invention should not be limited by any of the above-describedexemplary embodiments, but should be defined only in accordance with thefollowing claims appended hereto and their equivalents.

What is claimed is:
 1. A suture for repair of a tissue tear comprisingthree end USP size 6-0 polypropylene monofilaments intertwined withultra-high molecular weight polyethylene filaments, wherein thepolypropylene monofilaments comprises an angiogenic material inadmixture with the polypropylene, wherein the angiogenic material issodium butyrate and the monofilaments comprise 5% w/w of the sodiumbutyrate.
 2. The suture of claim 1, having the angiogenic precursormaterial impregnated into at least one region thereof.
 3. The suture ofclaim 1 wherein the suture is a sized No. 2 suture.
 4. The suture forrepair of a tissue tear according to claim 1, wherein upon placement ofthe suture within a mammalian organism, complete release of the sodiumbutyrate from the suture occurs within about 28 days.
 5. The suture forrepair of a tissue tear according to claim 1 wherein the ultra-highmolecular weight polyethylene filaments comprise monofilaments.
 6. Thesuture for repair of a tissue tear according to claim 1 wherein theultra-high molecular weight polyethylene filaments comprisemultifilaments.
 7. The suture for repair of a tissue tear according toclaim 1 wherein the polypropylene monofilaments are co-braided with theultra-high molecular weight polyethylene filaments.